Compound and method for treatment of movement disorders

ABSTRACT

The disclosed invention generally relates to pharmaceutical compounds and methods for treating and/or preventing diseases and disorders that often manifest in hyper and/or hypokinetic movements symptoms, as well as the method of administering therapeutically-effective amount of a pharmaceutical compound containing cannabinoids to subjects in need of treatment. The disclosed invention further relates to cannabinoid pharmaceutical compounds where said compound contains at least some non-cannabinoid components.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compounds and methodsfor treating and/or preventing diseases and disorders that oftenmanifest in hyper and hypokinetic movements symptoms, such asHuntington's Disease (HD) and Parkinson's Disease (PD), and topharmaceutical compounds and methods for treating and/or preventingsymptoms associated with said diseases and disorders.

BACKGROUND OF THE INVENTION

Cannabinoid (CB) components of marijuana are known to exert behavioraland psychotropic effects but also to possess therapeutic propertiesincluding analgesia, ocular hypotension, and antiemesis. CBs-basedmedications are now being used for treatment of a wide range of medicalconditions, including neuropathic pain, pain related to cancer andtrauma, spasticity associated with multiple sclerosis, fibromyalgia, andothers. This invention generally relates to treatment and/or preventionof hyper and hypokinetic movement symptoms associated withcannabinoid-responsive diseases and disorders in subjects in needthereof, as well as the method of administeringtherapeutically-effective amount of a pharmaceutical compound containingCBs.

CBs are a group of chemicals known to activate CB receptors in cells.These chemicals, which are found in cannabis plants, are also producedendogenously in humans and other animals, these are termedendocannabinoids. Synthetic CBs are chemicals with similar structures toplant CBs or endocannabinoids. Plant cannabinoids can also be isolatedsuch that they are “essentially pure” compounds. These isolated CBs areessentially free of the other naturally occurring compounds, such as,other minor CBs and molecules such as terpenes.

The methods and compounds of the proposed invention are intended fortreatment of multiple diseases, disorders, and conditions such as: HD;Wilson's Disease; Sydenham's Chorea; Chorea Gravidarum; AutosomalDominant Neurogenetic Syndrome; Huntington's Disease-Like Syndrome;Prion Disease; Spinocerebellar Ataxias; Neuroacanthocytosis;Dentatorubral-Pallidoluysian Atrophy; Brain Iron Accumulation Disorders;Friedreich's Ataxia; Mitochondrial Disease; Rett Syndrome;Cerebrovascular Disease; Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcal Infections (PANDAS); Levodopa-InducedDyskinesia (LID), anti-convulsants and anti-psychotics drugs-relatedsymptoms; Systemic Lupus Erythematosus; Antiphospholipid Syndrome;Tourette Syndrome (TS); Thyrotoxicosis; Polycythaemia Rubra Vera;Spongiform Encephalopathies; Coeliac Disease; PD; metabolic andendocrine-related diseases and disorders; athetosis-related to damage ordegeneration of basal ganglia; minor tranquilizers and alcoholwithdrawal syndromes; symptoms or side effects associated withanti-retroviral therapy, chemotherapy and radiation therapy.

Other diseases, disorders and conditions that cause athetosis, dystonia,tremors, tics, myoclonus, stereotypies, dyskinesia, restless legssyndrome, and Periodic Limb Movement Disorder (PLMD) are alsocontemplated by the invention. In addition, the methods of the inventionmay be used to alleviate, or relief symptoms or side effects associatedwith anti-retroviral therapy, chemotherapy, radiation therapy, andtreatment of chemical withdrawal. Certain diseases and disorders arebriefly outlined below, and the possible mechanisms of CB action areexemplified with treatment of certain diseases that cause hyperkineticor hypokinetic movement symptoms.

Most hyperkinetic and hypokinetic movement disorders are caused by adysfunction of basal ganglia-thalamo-cortical loops. Central CBreceptors are located in large quantities in the output nuclei of thebasal ganglia (globus pallidus, substantia nigra pars reticulata). Itsuggests that they could be involved in the regulation of motoractivity. There is evidence that endogenous CB transmission plays a rolein the manipulation of other transmitter systems within the basalganglia by increasing GABAergic transmission, inhibiting glutamaterelease and affecting dopaminergic uptake.

In recent years a limited number of clinical trials in humansdemonstrated that CBs might be useful in the treatment of movementdisorders. It has been suggested that an endogenous CB tone participatesin the control of movements and, therefore, the central Endo-CannabinoidSystem (ECS) might play a role in the pathophysiology of these diseases.There is also limited evidence that CBs are of therapeutic value in thetreatment of tics in TS, the reduction of LID in PD and some forms oftremor and dystonia. There is also evidence that CBs are useful in thetreatment of chorea in HD and hypokinetic parkinsonian syndromes.Currently, treatments of these and similar diseases are focused onrelieving symptoms and preventing complications because there is nocurative therapy. Medical interventions include: physical therapy,immunosuppressive medication, hormone replacement therapy, bloodtransfusions (if blood is affected), anti-inflammatory medication, painmedication, and others.

Preclinical research in animal models of several movement disorders haveshown variable evidence for symptomatic benefits but more consistentlysuggest potential neuroprotective effects in several animal models of PDand HD. Clinical observations and clinical trials of CB-based therapiessuggest a possible benefit of CBs for tics.

The primary CB receptor subtypes are CB receptors type 1 (CB1) and type2 (CB2). CB1 receptors are highly expressed in the Central NervousSystem (CNS), especially the basal ganglia, and also identified inalmost all peripheral tissues and cell types. CB2 receptors areexpressed primarily in the immune system, where they modulateinflammation, but are also expressed in the CNS, particularly in neuronswithin the dorsal vagal motor nucleus, the nucleus ambiguous, the spinaltrigeminal nucleus, and microglia. CB2 receptors were also found in thebasal ganglia and studies suggest that impairment of these receptors maybe associated with dyskinesia. While most actions of CBs are related toCB1 and CB2 receptors, other receptor types have been described,including the Transient Receptor Potential Vanilloid type 1 (TRPV1)cation channel, the GTP-binding Protein-coupled Receptor GPR55, theabnormal-CBD receptor, and the Peroxisome-Proliferator-ActivatedReceptor (PPAR). (Kluger, Triolo, Jones, & Jankovic, 2015)

Endogenously produced CBs (eCBs) are lipophilic compounds thatdemonstrate varying degrees of affinity for G-protein coupled CBreceptors and include anandamide and 2-arachidonoglycerol. eCBsprimarily function through retrograde signaling, wherein post-synapticactivity leads to eCB production and release with backward transmissionacross the synapse to depress presynaptic neurotransmitter release. TheECS may also support synapse formation and neurogenesis. Within thebasal ganglia, eCBs and CB1 receptors tend to increase GABAergic andinhibit glutamatergic transmission. eCBs also tend to inhibit dopaminerelease through GABAergic mechanisms. eCBs are not stored and arequickly degraded after exerting a transient and localized effect.Removal of eCBs from the extracellular space occurs through cellularuptake and metabolism with anandamide degraded primarily by Fatty AcidAmide Hydrolysis (FAAH) and 2-AG degraded by monoacylglycerol lipase.(Kluger, Triolo, Jones, & Jankovic, 2015)

According to Kluger, Triolo, Jones, and Jankovic, and as furthersuggested in the preclinical studies shown in FIG. 3, a number of PD andHD studies in animal models suggest that CB-based therapies may reduceneurodegeneration and reduce hyperkinetic activity. (Kluger, Triolo,Jones, & Jankovic, 2015) The U.S. Pat. No. 6,630,507 referenced herein,provides a list of CBs useful in certain neurodegenerative diseases suchas PD, Alzheimer's Disease (AD), and dementia caused by humanimmunodeficiency virus. A number of recent studies conclude that CBs mayoffer neuroprotection through both receptor-mediated andreceptor-independent mechanisms. According to Sagredo, et al., CBs arecapable of reducing oxidative damage by acting as scavengers of ReactiveOxygen Species (ROS) and enhancing endogenous antioxidant defenses.(Sagredo, et al., 2007) Certain CBs, such as CBD and THC may appear toexhibit this property independent of CB1 and CB2 receptor modulation.These CBs also exhibit anti-inflammatory effects by inhibiting reactivemicroglia and cytokine release. There is also evidence that CB1 agonistsreduce excitotoxicity by suppressing glutamatergic activity, subsequentcalcium ion influx, and nitric oxide production. (Romero & Orgado, 2009)

Experimental animal models indicate that HD is associated with early andwidespread reductions in the ECS, particularly CB1 receptors in thestriatum. CB1 receptors mediate brain-derived neurotrophic factorexpression and CB1 receptor loss is associated with exacerbation ofsymptoms, neuropathology, and molecular pathology in the striatum.Moreover, CBs-based therapies generally show neuroprotection in severalanimal models through both CB receptor mediated and independent effects.(Kluger, Triolo, Jones, & Jankovic, 2015) Therapeutic studies ofCB-based agents in HD animal models suggest that CB1 and endovanilloidreceptor agonists, and anandamide reuptake inhibitors are capable ofalleviating hyperkinesia. This therapeutic potential is likely to berealized in early phases of HD because of progressive loss of CB1receptors in advanced stages. (Lastres-Becker, et al., 2001)

Experimental models of PD show increased ECS activity in the basalganglia, including increased CB1 mRNA levels, CB1 activity, anandamidelevels, and decreased CB clearance. These changes appear to beassociated with movement suppression and may be reversed by chroniclevodopa treatment. Importantly, many CBs demonstrate neuroprotectiveeffects in several models of PD. These effects appear to be mediated byboth CB receptor dependent and independent mechanisms includingantioxidant effects, reduced microglia activation, and modulation ofglial-neuron interactions. (Kluger, Triolo, Jones, & Jankovic, 2015)Animal studies further suggest that CBs may improve motor symptoms of PDand LID. CB1 agonists inhibit basal ganglia dopamine release and aretherefore could be ineffective in alleviating PD motor symptoms. Indeed,CB1 agonists have been shown to exacerbate bradykinesia in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates.(Meschler, Howlett, & Madras, 2001)

However, CB1 agonists have also been reported to improve motorimpairments, possibly through nondopaminergic mechanisms includinginteractions with adenosine A2A receptors. Studies of CB1 antagonistsare more consistent in improving motor symptoms without increasingdyskinesias. These effects appear to involve nondopaminergic mechanismsincluding enhanced striatal glutamate release and may be greater inanimals with more severe striatonigral degeneration. (Kluger, Triolo,Jones, & Jankovic, 2015)

It is conceivable that CB1 agonists also reduce overactivity of theglobus pallidus interna and improve dystonia by reducing GABA reuptake.In support of this idea, the CB1 and CB2 agonist WIN55,212-2 producesantidystonic effects in a mutant hamster model of dystonia, increasesthe antidystonic efficacy of benzodiazepines and is reversed byrimonabant, a selective CB1 antagonist. Animal models suggest that CBsmay reduce Multiple Scleroses (MS)-related tremor, an effect thatappears to be selectively mediated by CB1 receptors.

Case reports of smoked cannabis, oral THC, and case series of smokedcannabis suggest that CBs may be beneficial for tics in patients withTS. Similarly, a survey of 64 TS patients found that 17 (27%) had triedmarijuana and 14 of them (82%) found it helpful for tics and behavioraldisturbances. (Muller-Vahl, Kolbe, Schneider, & Emrich, 1998) There isalso evidence suggesting that CBs may be effective for ataxia, myoclonusor restless legs syndrome. Two case reports suggest ataxia (incombination with spasticity) in MS may improve following smoked cannabisor oral THC. (Meinck, Schonle, & Conrad, 1989)

It was discovered that glutamate toxicity could be prevented to someextent by isolated or synthetic THC or CBD. (Hampson, Grimaldi, Axelrod,& Wink, 1998) The CBs were also tested in vitro on neuronal culturesexposed to glutamate. CBD and other CBs were examined asneuroprotectants in rat cortical neuron cultures exposed to toxic levelsof the neurotransmitter, glutamate.

According to Hampson, et al., the psychotropic CB receptor agonist delta9-THC and a non-psychoactive constituent of marijuana—CBD, both reducedthe n-methyl-d-aspartic acid (NMDA) anda-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors,as well as kainate receptor mediated neurotoxicity. Neuroprotection wasnot affected by CB receptor antagonist, indicating a CBreceptor-independent mechanism of action. (Hampson, et al., 2000)

Glutamate toxicity can be reduced by antioxidants. Using cyclicvoltammetry and a fenton reaction-based system, it was demonstrated thatCBD, THC and other CBs are potent antioxidants. As evidence that CBs canact as antioxidants in neuronal cultures, CBD was demonstrated to reducehydroperoxide toxicity in neurons. In a head to head trial of theabilities of various antioxidants to prevent glutamate toxicity, CBD wassuperior to both alpha-tocopherol and ascorbate in protective capacity.The preliminary studies in a rat model of focal cerebral ischemiasuggest that CBD may be at least as effective in vivo as seen in thesein vitro studies. (Hampson, et al., 2000)

The example illustrated in FIG. 2, incorporated herein by reference,compares the oxidation potentials of CBs and the antioxidant ButylatedHydroxytoluene (BHT). Effect of CBD and THC on dihydrorhodamineoxidation. CBs were compared with BHT for their ability to preventtert-butyl hydroperoxide-induced oxidation of dihydrorhodamine. Thisexperiment was repeated four times with essentially the same results.(Hampson, Grimaldi, Axelrod, & Wink, 1998)

A study by Formukong, Evans, & Evans was undertaken to determine theanalgesic and anti-inflammatory activity of various CBs and CBpre-cursors. Oral administration of CBD was found to be the mosteffective at inhibition of phenyl-p-benzoquinone-induced writhing inmice. THC and CBN were found to be least effective at reducing analgesiaand inflammation. (Formukong, Evans, & Evans, 1988) Another studyundertaken by Hampson, Grimaldi, Axelrod, & Wink, as exemplified in FIG.1, incorporated herein by reference, compares the oxidation potentialsof CBs and the antioxidant BHT. (Hampson, Grimaldi, Axelrod, & Wink,1998)

Further, certain anecdotic evidence suggests that CB-containing plantextracts are demonstrating higher efficacy in treatment of someneurodegenerative diseases than essentially pure CBs. Specifically,CB-containing plant extracts comprising, as a predominant CB, THC andCBD—particularly effective in the retardation of neural degeneration.

Several pharmaceutical products exist which contain eitherphytocannabinoids (natural) or synthetic CBs. For example, dronabinol(Marinol) is the International Nonproprietary Name (INN) for anencapsulated THC product which has been used therapeutically as anappetite stimulant, antiemetic, and analgesic, either as an inhalant oras an oral drug. Also, nabilone (Cesamet) is a synthetic analog ofdronabinol (Marinol), while Sativex is a CB extract oral spraycontaining THC, and other CBs that are used to treat neuropathic pain,spasticity, nausea associated with cancer chemotherapy, and stimulateappetite in HIV patients.

Further, rimonabant (marketed under various tradenames) is a selectivecannabinoid receptor antagonist used as an anti-obesity drug and as asmoking cessation. Several other cannabinoid-containing products exist.

Thus, considering the therapeutic effect of compounds containing CBs,especially (—)-Δ⁹-trans-THC, there is a continuing need for improvingexisting CB-containing products as well as a need for new products anddelivery systems containing CBs, especially in the pharmaceutical field.

The use of cannabis as a medicine has long been known and during the19^(th) century preparations of cannabis were recommended as a hypnoticsedative which were useful for the treatment of hysteria, delirium,epilepsy, nervous insomnia, migraine, pain and dysmenorrhea. Untilrecently the administration of cannabis to a patient was mainly achievedby preparation of cannabis by decoction in ethanol, which could then beswallowed or by the patient inhaling the vapors of cannabis by smokingthe dried plant material.

It is important to note that side effects, as well as therapeuticeffects, vary depending on the CBs, concentration of CBs, or ratio ofCBs in formulations. Smoking cannabis has been associated with lungcancer risk, although oral administration is also problematic due todeposition of CBs into fatty tissue, from which they are releasedslowly, causing variability in plasma concentrations. (Kluger, Triolo,Jones, & Jankovic, 2015) There is also an important risk of abuse withmarijuana and cannabis-based drugs due to the psychotropic effect ofTHC. (Haberstick, et al., 2014) Studies of marijuana outside of themedical context estimate 9% of persons using cannabis may becomeaddicted and experience symptoms of withdrawal after quitting the drug.(Warner, Kessler, Hughes, Anthony, & Nelson, 1995) These, along withlegal issues, are some of the main difficulties today in treatingpatients with natural CBs. Inconsistent drug delivery systems (smoking,oral sprays, inhalers, and others), inconsistent compounds due to thenatural variances of CBs, inherent instability of certain CBs, as wellas abuse potential due to the psychotropic effect, are some of the areasthat this invention aims to overcome by providing a standardized,medical-grade CB-based pharmaceutical and delivery system for effectivetreatment of movement disorders with minimal psychotropic effect andtherefore abuse potential.

Recent methods have sought to find new ways to deliver CBs to a patientincluding those which bypass the stomach and the associated first passeffect of the liver which can remove up to 90% of the active ingesteddose and avoid the patient having to inhale unhealthy tars andassociated carcinogens into their lungs. Such dosage forms includeadministering the CBs to the sublingual or buccal mucosae, inhalation ofa CB vapor by vaporization or nebulization, enemas or solid dosage formssuch as gels, capsules, tablets, pastilles and lozenges.

To attain the required purity of isolated CBs, up to at least 95% bytotal weight, consistent ratio of CBs in the formulation, attainpharmaceutical-grade stability of active CBs, effective and consistentdelivery system for treating multiple conditions, as well astherapeutically-effective treatment methods—requires a know-how that isproposed in this document. However, there is existing prior art, such aspatents, published patent applications, academic work, and other, thatis related but distinct from the proposed invention.

The U.S. Pat. No. 7,449,589, referenced herein, demonstrates one of manyprocesses for purifying (-)-Δ9-trans-tetrahydrocannabinol and showsvarious cannabinoid compounds, including THC, CBD, and CBN. The THCreportedly has at least eight individual isomers of which(-)-Δ9-trans-tetrahydrocannabinol ((-)-Δ9-trans-THC) is the main andmost active isomer. Although Δ8-tetrahydrocannabinol has similaractivity as (-)-Δ9-trans-THC, it is only approximately 75% as potent andalso tends to degrade to other compounds including CBN. (U.S. Pat. No.7,449,589 B2, 2004)

The U.S. Pat. No. 8,628,796, referenced herein, discloses anencapsulated THC composition, including (-)-Δ9-trans-THC purportedlyhaving improved stability. The disclosure emphasizes that the stabilitycan be improved by including bases (e.g., amines) in the formulation. Inaddition, the stability of the compositions disclosed is best preservedby storing the compositions in a sealed container, such as in a capsule,and under refrigerated conditions.

Specifically, the disclosure asserts that one embodiment of theinvention described therein overcomes the deficiencies of prior art oraldosage forms containing (-)-Δ9-trans-THC by utilizing hard gelatincapsules, instead of soft gelatin capsules. As stated in the disclosure,unlike soft gelatin capsules, hard gelatin capsules do not containglycerol—a major cause of instability for the active (-)-Δ9-trans-THCpharmaceutical ingredient. The disclosure purports to provide a stableproduct, such as one that does not degrade to an unacceptable extentduring the desired shelf-life of the dosage form. (US Patent No. U.S.Pat. No. 8,628,796 B2, 2005)

The U.S. Pat. No. 7,968,594, referenced herein, discloses the inventionthat relates to treatment of cancer related pain and constipation. Thesubject in need is administered a combination of CBD and delta-9-THC ina predefined ratio by weight of approximately 1:1 of CBD to THC. (U.S.Pat. No. 7,968,594 B2, 2005)

The U.S. Pat. No. 9,205,063, also published as the U.S. Pat. No.8673368, referenced herein, discloses in one aspect, a method thatrelates to use of one or more CB-containing plant extracts consistingessentially of an extract of Cannabis sativa obtained by supercriticalor subcritical extraction with CO2; and where said extract is used inthe prevention or treatment of neural degeneration, wherein the one ormore CB-containing plant extracts comprise a CB-containing fraction,consisting essentially of the major CB, a minor CB, and one or moreother CBs, and a non-CB containing fraction. (U.S. Pat. No. 9,205,063B2, 2014) (U.S. Pat. No. 8,673,368 B2, 2007)

The U.S. Pat. Application No. 20,140,228,438, referenced herein,discloses the invention that relates to CBs for use in the prevention ortreatment of neurodegenerative diseases or disorders. Preferably, theCBs are cannabichromene (CBC) cannabidivarin (CBDV) and/orcannabidivarin acid (CBDVA). More preferably, the neurodegenerativedisease or disorder to be prevented or treated is Alzheimer's Disease.(US Patent No. US20140228438 A1, 2012)

The U.S. Pat. Application No. 20,060,135,599, referenced herein,discloses the invention that relates to the use of one or more CBs inthe treatment of neuropathic or chronic pain. A method of treatingbrachial plexus avulsion in a human patient comprising administering toa patient in need thereof effective amount one or more CBs. (US PatentNo. US20060135599 A1, 2003)

The U.S. Pat. No. 8,980,940, referenced herein, discloses a compositioncomprising a high purity CB, an acid, and a pharmaceutically-acceptablesolvent that achieves room temperature stability for over 24 months. Theacid improves the stability of the composition and the solvent enhancesthe solubility of the acid, thereby allowing the acid to have animproved stabilizing effect on the highly pure CB. Preferably, thesolvent is an alcohol and, more preferably, the composition contains anoil. A method for making the composition includes combining the CB andthe solvent and evaporating a portion of the solvent, along with addingan acid to the composition, before, during, or after the evaporatingstep. A method for making and storing the composition includes storingthe composition in a manner adapted to maintain its stability. (U.S.Pat. No. 8980940 B2, 2011)

The U.S. Pat. Application No. 20,080,175,902, referenced herein,discloses methods for slowing the progression of MS comprisingadministering a therapeutically effective amount of CB to a patientsuffering from MS. A method of slowing the progression of MS in apatient in need thereof, comprising administration of a pharmaceuticalcomposition containing an effective amount of therapeutically effectiveCB on a regular basis; the administration occurring over a period oftime: at least about 16 weeks, at least about 27 weeks, at least about40 weeks and at least about 52 weeks. (US Patent No. US20080175902 A1,2007)

The U.S. Pat. Application No. 20,060,167,084, referenced herein,discloses methods of, inter alia, treating and/or preventing symptomsassociated with MS and its relapse. A method of treating and/orpreventing symptoms associated with MS in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition comprising delta-9-THC.(US Patent No. US20060167084 A1, 2005)

The U.S. Pat. Application No. 20,040,018,151, referenced herein,discloses in one aspect, a method for promoting normal motor function inAmyotrophic Lateral Sclerosis (ALS) patients. The method comprisesadministering a compound that is an anandamide/CB receptor/acceptoragonist to a mammal having observable motor function, and evaluating oneor more indicia of motor function in said mammal, wherein a compoundthat promotes normal motor function is identified. More preferably, themammal to which the administration is made has one or more ALS or MotorNeuron Disease (MND) symptoms and such one or more symptoms include atleast one of the observable motor functions being evaluated. (US PatentNo. US20040018151 A1, 2003)

SUMMARY OF THE INVENTION

The following description presents a simplified view of one or moreaspects of the proposed invention. This summary is not an extensiveoverview of all contemplated embodiments and implementations. It isintended to neither identify key or critical elements of all features,nor delineate the scope of any or all facets. Its sole purpose is topresent some concepts of one or more aspects in a simplified form.

A CB-containing plant extract contains in addition to one or more otherCBs, one or more non-CB components which are co-extracted with the CBsfrom the plant material. Their respective ranges will vary according tothe starting plant material and the extraction methodology used.CB-containing plant extracts may be obtained by various means ofextraction of cannabis plant material. Such means include but are notlimited to: supercritical or subcritical extraction with CO2, extractionwith hot gas, and extraction with solvents. The terms“cannabinoid-containing plant extract”, or “cannabinoid extract”, or“cannabis extract”, or Cannabis plant, or similar are taken herein torefer to one or more plant extracts from any plant in the Cannabaceaefamily or any plant that contains any form of THC and/or CBD.

It was discovered, that the use of a cannabis extract that contains THCand CBD in the ratio of approximately 1 (THC) and 2 (CBD) by weigh, orTHC and CBD in the ratio of 0.5 to 1 (THC) and 1.5 to 2 (CBD) by weight,or THC and CBD in the ratio of 1 to 1.5 (THC) and 2 to 2.5 (CBD) byweight; and in addition contains one or more other CBs and one or morenon-CB components that are co-extracted with the CBs from the plantmaterial is more effective in the treatment of hyper and hypokineticmovement symptoms in the aforementioned diseases and disorders than amedicinal extract containing pure THC.

It was also discovered that some of the unwanted side effects caused bycurrently available medications are reduced or eliminated by treatmentwith the compound disclosed herein, for example: Marinol in the case ofMS, opiates in the case of cancer and trauma, Tetrabenazine andBenzodiazepine in the case of HD, and others.

In one embodiment of the proposed invention, the treatment of HD choreainvolves giving to a patient in the morning by oral administration a onesoft-gel capsule of the compound containing a mixture of delta-9 anddelta-8-THC and the CBD in the ratio of approximately 0.7 and 2 byweigh, and such mixture contains a small amount of other CBs, and in oneembodiment, one or more non-CB components, such as sesame oil, wheresuch capsule is a time-released capsule designed to release said mixturein the small intestine; and in another embodiment, in the stomach; andin another embodiment, as exemplified in FIG. 4. The aforesaid compoundand method in some subjects may reduce symptoms associated with, in oneembodiment, HD chorea, having minimal to nonexistent psychotropiceffect.

In another embodiment of the proposed invention, the treatment of LID,such as a common side effect of PD levodopa treatment, involves givingto a patient before bed time by oral administration a dose ofmedicament—in one embodiment, one extended release soft-gel capsule andone immediate release soft-gel capsule of the compound containing amixture of delta-9-THC and CBD in the ratio of approximately 1.5 and 2by weigh, and such mixture contains a small amount of other CBs, and inone embodiment, one or more non-CB components, such as sesame oil. Thismethod provides effective control of symptoms at bed time with a desiredmild psychotropic effect acting as a sleeping aid.

In another embodiment of the proposed invention, the treatment of MSspasticity involves giving to a patient two times a day by oraladministration a dose of medicament, in one embodiment, a soft-gelatincapsule that consists of type A and/or B gelatin, water, and aplasticizer, such as glycerin or sorbitol; and encapsulates a compoundcontaining a liquid mixture that includes: 10 mg of delta-9-THC and 20mg of CBD, some sesame oil, some methyl and propyl parabens, some othercannabinoids and some other substances that are cumulatively less than5% of the overall mixture, or as in one embodiment exemplified in FIG.4.

The proposed invention provides methods and compounds for treatment ofmultiple diseases and disorders at various stages with differentpatients potentially presenting different motoric dysfunction symptoms,and as such requiring larger or smaller doses to achieve the desiredefficacy. Besides, certain variations of THC/CBD ratios and othercomponents may be required to achieve the desired effect, such as thenight or day-time application.

In one aspect of the invention, titration of doses is beneficial topatients as they can take smaller doses of the medication to achieveefficacy. It is understandable that not all patients will require thesame dose of medication; for example, patients of a larger build orfaster metabolism may require a higher dose than that required by apatient that is of a smaller build or slower metabolism. In oneembodiment said titration is adjusted with a time-release and point ofrelease-tailored dosage forms. For instance, a gelatin capsule or atablet designed to release medication in doses in certain parts of thedigestive system to achieve the desired efficacy.

In another embodiment, the dose of medicament to be administered to asubject suffering from HD-related chorea is formulated such that aspecific patient can titrate such dose; where the term “titrate” meansthat the patient is provided with a medication that is in such a form orengineered in such a way that smaller doses than the unit dose can betaken. In one embodiment, the titratable dosage forms are gel, gelspray, transdermal patch, liquid, vapor, spray, and the like.

The unit dosage—defined as a maximum dose of medication that can betaken at any one time or within a specified dosage period—may range, inone embodiment, between 20 and 60 mg of said medicine, or, depending onthe administration route and aforesaid variables, the dosage mayfluctuate significantly, such that unit dosage may consist of multipledoses taken several times a day. Administration of the compound may becarried out by any of several suitable known means, including but notlimited to intraperitoneal, subcutaneous, oral, intramuscular,intravenous, and others.

These and other embodiments and objects of the invention will becomeapparent upon further review of the specification and claims presentedherein. Thus, the above and the following expressed embodiments andobjects of the invention are not intended by the inventors to limit thescope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate aspects of the present teachingsand together with the description, serve to explain principles of thepresent teachings.

The FIG. 1, incorporated herein by reference, compares the oxidationpotentials of CBs and the BHT. The oxidation profiles of (750 μM) BHT,CBs, and anandamide were compared by cyclic voltammetry. Anandamide, aCB receptor ligand with a non-CB structure, was used as a nonresponsivecontrol. Experiments were repeated three times with essentially the sameresults. (Hampson, Grimaldi, Axelrod, & Wink, 1998)

The FIG. 2, incorporated herein by reference, compares the oxidationpotentials of CBs and the antioxidant BHT. Effect of CBD and THC ondihydrorhodamine oxidation. CBs were compared with BHT for their abilityto prevent tert-butyl hydroperoxide-induced oxidation ofdihydrorhodamine. Data represent mean values±SEM from a singleexperiment with three replicates. This experiment was repeated fourtimes with essentially the same results. (Hampson, Grimaldi, Axelrod, &Wink, 1998)

The FIG. 3, incorporated herein by reference, shows the results ofcertain preclinical studies assessing therapeutic symptomatic efficacyof CBs for HD chorea. (Kluger, Triolo, Jones, & Jankovic, 2015)

The FIG. 4, incorporated herein by reference, shows a variable-releasesoft-gelatin capsule pill, one of many possible dosage forms, thatconsists of predominantly type A or B gelatin, water, sorbitol, andencapsulates a compound containing a liquid mixture that includes: 10 mgof THC and 20 mg of CBD, some sesame oil, some methyl/propyl parabens,and less than 5% of some other CBs and some other substances.

DESCRIPTION OF EMBODIMENTS

Reference will now be made to embodiments, examples of which areillustrated in the accompanying drawings. In the following description,some details are set forth in order to provide understanding of theproposed invention. However, it will be apparent to one of ordinaryskill in the art that the present invention may be practiced withoutthese details. In other instances, well-known methods, procedures, andcomponents have not been described in detail so as not to unnecessarilyobscure aspects of the embodiments.

It will also be understood that, although the terms first, second, etc.,may be used herein to describe various elements, these elements shouldnot be limited by these terms. These terms are only used to distinguishone element from another. For example, a first contact could be termed asecond contact, and, similarly, a second contact could be termed a firstcontact, without departing from the scope of the present invention. Thefirst contact and the second contact are both contacts, but they are notthe same contact.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and it is notintended to be limiting of the invention. As used in the description ofthe invention and the appended claims, the singular forms “a,” “an,” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise. Moreover, the term “or” is intendedto mean an inclusive “or” rather than an exclusive “or.” That is, unlessspecified otherwise, or clear from the context, the phrase “X employs Aor B” is intended to mean any of the natural inclusive permutations. Itwill also be understood that the term “and/or” as used herein refers toand encompasses any and all possible combinations of one or more of theassociated listed items. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, integers, steps, operations,elements, and/or components, but do not preclude the presence oraddition of one or more other features, integers, steps, operations,elements, components, and/or groups thereof.

As used herein, the term “if” may be construed to mean “when” or “upon”or “in response to determining” or “in response to detecting,” dependingon the context. Similarly, the phrase “if it is determined” or “if isdetected” may be construed to mean “upon determining” or “in response todetermining” or “upon detecting (the stated condition or event)” or “inresponse to detecting (the stated condition or event),” depending on thecontext.

As used herein, the terms “related”, “in connection”, or “associated”,or “relevant”, and similar, depending on the context, means anyassociation, whether direct or indirect, by any applicable criteria asthe case may be.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration”. And no aspect of this disclosure shall beconstrued as preferred or advantageous over other aspects or designsunless expressly stated.

CBs are compounds usually derived from Cannabis sativa, an annual plantin the Cannabaceae family. The plant contains more than 420 differentcomponents, with at least 61 compounds of these belonging to the classof CBs. The most active naturally occurring CBs are THC and CBD, whichcould possibly be used for the treatment of a wide range of medicalconditions, including neuropathic pain, symptoms of hyper andhypokinetic movement diseases and disorders, fibromyalgia, and others.

The present invention provides a treatment method of certain diseasesand disorders, as well as a pharmaceutical compound that represents astable, slow and fast-acting formulations of CBs or its derivatives,prodrugs, or analogs (for the purpose of this document, may be usedinterchangeably). An analog herein refers to a compound that is derivedfrom a naturally occurring CB by chemical, biological or synthetictransformation of the naturally occurring CB or a synthetic or apartially synthetically derived substance that is similar or nearsimilar to a CB in question. According to one aspect, therefore, liquidcompounds of CBs are provided in certain rations as disclosed herein.

Illustrative of CBs or CB analogues are compounds selected from thegroup consisting of cannabinol, cannabidiol, Δ8-tetrahydrocannabinol,Δ9-tetrahydrocannabinol, 11-hydroxy-tetrahydrocannabinol,11-bydroxy-Δ9-tetrahydrocannabinol, levonantradol,Δ11-tetrahydrocannabinol, tetranydrocannabinol, tetrahydrocannabivarin,dronabinol, amandamide, nabilone, a combination thereof, a natural orsynthetic analogue or equivalent thereof, and a natural or syntheticmolecule with a basic CB structure.

The natural CB compounds are readily obtained from plant tissue bysuspending the tissue in an appropriate solvent to extract CB compoundsand other tissue components. Analytical purification of such an extractprovides pharmaceutical grade CB compounds. Alternatively, CB compoundsare extracted from plant tissue under supercritical conditions. Solventsused for supercritical extraction of CBs include, for instance: carbondioxide, or other gases in isolation or combination with or withoutsolvent modifiers, selected from ethanol, propanol, butanol, hexane,chloroform, dichloromethane, acetone, or any organic solvent capable ofextracting CB s, and alcohol-water mixtures, such as water-ethanol orwater-butanol mixtures, etc.

The present invention, in one embodiment, involves producing an extractfrom cannabis plant matter, containing THC, CBD and optionally thecarboxylic acids thereof. In one embodiment, the dried plant matter isground and subjected to a CO2 extraction and the primary extractobtained is separated. Specifically, ground Cannabis plant material iscompressed and charged into an extraction vessel. CO2 is thenintroduced, having been brought to a temperature, in one embodiment, ofapproximately 60° C. and to a pressure of approximately 250 bars. Whenthe CO2 enters into contact with the material to be extracted, itextracts the desired CB components, in particular comprising Δ9-THC andCBD, as well as the carboxylic acids thereof. In one embodiment, theextraction method permits extracting various isomers of THC, selectivelyobtained from industrial hemp and from drug-producing hemp, alsoseparating undesirable waxes and removing the solvent.

CBs, including THC, can be isolated from Cannabis plants using the CO2extraction or any other extraction method, or can be madesemi-synthetically. It is preferable, in one embodiment, that theextraction/production method yields substantially the (-)-Δ⁹-trans-THCisomer that is the most active isomer of THC. There are also varioustechniques that are known for isolating and separating the(-)-Δ⁹-trans-THC isomer from other compounds in THC. For example, U.S.Pat. No. 7,449,589 describes methods for purifying the (-)-Δ⁹-trans-THCisomer from a mixture of other THC isomers. (U.S. Pat. No. 7,449,589 B2,2004)

However, THC, and in particular the (-)-Δ⁹-trans-THC isomer, is veryunstable. Also, chemical synthesis and isolation of (-)-Δ⁹-trans-THC areboth challenging. The (-)-Δ⁹-trans-THC isomer is very prone toacid-catalysed isomerization to the Δ⁸-THC isomer, is easily oxidized byoxygen to form inactive cannibinol, and is also sensitive to light andheat. All of these factors make it difficult to synthesize, purify, andstore a high purity THC compound comprising the (-)-Δ⁹-trans-THC isomerwhich is stable over time and under various storage conditions.

It is not the purpose of present disclosure to provide particularsconcerning the attainment of a colloidal formulation that is stableunder a range of conditions. Though, in one embodiment, the disclosedcompound with initial purity (HPLC) of THC and CBD being at least 98% byarea can achieve stability such that at least 95% by area remains inundegraded form after exposure of the compound to the storage conditionsfor twelve months, where the ambient temperature is between 20° C. and40° C. and relative humidity is between 55% and 75%.

In one embodiment, the stability of said compound is attained bycontacting a solution containing CBs into a solvent such as water, C1-C₆aliphatic alcohols, or mixtures of water and alcohols, acetone, or otherwater-miscible organic solvents that can be used to dissolve the CBs;and in another embodiment, with addition of pharmaceutically acceptablebuffers, stabilizers, and other pharmacologically inactive substances.

In one embodiment, the inventive CB compound is in the form of micellesor liposomes that encapsulate a CB within the membrane of the micellesor liposomes. Within the context of the present technology, the term“micelle” refers to an aggregate of surfactant molecules dispersed in aliquid colloid, while “liposome” refers to a vesicle composed of a monoor bilayer lipid.

In yet another embodiment, other drugs and pharmaceutically acceptablecarriers, if present, may be in the lipophilic membrane or entrapped inthe aqueous fluid that forms the core of the liposome. The entrapped CBscontribute to the stability of the micelle/liposome membranes, such thatthe micelle/liposomes formulations may be used as an improved, fast,reliable and efficient system for the oral, enteral, parenteral,intravenous or topical delivery of CBs and/or additional drugs tosubjects in need thereof. The term “subject” or “patient” refers to amammal in need of treatment or undergoing treatment using the inventivecompounds described herein. Mammalian subjects include withoutlimitation humans, dog, cat, horse or any other animal in need oftreatment.

In another embodiment, unilamellar micelles or liposomes that arethermostable at temperatures greater than 50° C. are used in themanufacture of CB compound, according to the present invention. Thesemicelles or liposomes are obtained by contacting a solution of CB (a CBplant extract) with an aqueous solvent or an aqueous solution of apharmaceutically active compound or drug. The mixing of CB solutionoccurs in a manner suitable for the rapid dissolution of CB solution inthe aqueous solution. This can be accomplished through a variety ofmeans, including dilution, injection through a small orifice underpressure, and ultrasonic atomization.

And yet in another embodiment, the disclosed compound has advantageousproperties, where the micellar and liposomal compound is stable at hightemperatures, exceeding 50° C., is stable to sonication, capable ofcarrying large payloads of CBs as well as other drugs suitable for usein combination therapy and can be stored for extended periods of time,for example greater than 20 weeks at 25° C.

In certain embodiments, said compound can be in the form of aconcentrated, stable colloidal suspension that is obtained by infusing asolvent solution containing the CB plant extract or pure CBs into asolvent such as water, with or without buffer. Stabilizing agent, forinstance, a polymer or compounds selected from cellulose hyaluronicacid, polyvinyl pyrrolidone (PVP), alginate, chondritin sulfate, polygamma glutamic acid, gelatin, chitisin, corn starch and flour can beused to stabilize the micelle formulations.

In one embodiment, said compound also exhibits superior systemicdelivery and release of CBs from the micelle or liposomes used in themanufacture of the inventive compound. The release of a CB from aliposome or micelle of the inventive compound can be modulated bychanging the ratio of the concentration of lipid to the concentration ofCB present in the liposome.

In one embodiment, tissue specific delivery can be achieved by modifyingthe surface of the liposomes or micelles with compounds that bindspecifically to biological macromolecules expressed on cellularsurfaces. For instance, the micelle or liposomal surface can bederivatized to display an antibody specific to an antigen expressed oncancer cells.

According to one embodiment, said compound that is used in the treatmentof a disease condition is administered to a patient or subject in needof treatment either alone or in combination with other compounds/drugshaving similar or different biological activities. For example, saidcompound may be administered in a combination therapy, i.e., eithersimultaneously in single or separate dosage forms or in separate dosageforms within hours or days of each other. Examples of compounds/drugsused in such combination therapies include without limitation:chemotherapeutic agents, immunosuppressive agents, immunostimulatory,anti-pyretic, cytokines, opioids, cytokines, cytotoxic agents,nucleolytic compounds, radioactive isotopes, receptors, pro-drugactivating enzymes, which may be naturally occurring or produced byrecombinant methods, anti-inflammatory agents, antibiotics, proteaseinhibitors, growth factors, osteo-inductive factors and the like.

In some embodiments, the compound further contains, in accordance withaccepted practices of pharmaceutical compounding, one or morepharmaceutically acceptable excipients, including without limitation:diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants,buffers, flavor imparting agents. As stated above, said compound maycontain a CB, a CB analog or both, and may be consumed directly orformulated into nutraceutical or pharmaceutically acceptable compoundssuitable for oral, enteral, parenteral, intravenous, topical, or otheradministration.

The term “parenteral” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Such excipients are well known in the art. Dosage forms fororal administration include food, beverages, drinks, soups, baked goods,syrups, oral pharmaceutical compounds, nutraceutical formulations, andthe like. Suitable pharmaceutical carriers include any such materialsknown in the art, e.g., any liquid, gel, solvent, liquid diluent,solubilizer, polymer or the like, which do not significantly interactwith other components of the formulations in a deleterious manner.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, solutions, suspensions,syrups and elixirs. In addition to the CB plant extract, the liquiddosage forms may contain inert diluents commonly used in the art. Forinstance, liquid formulations can contain water, alcohol, polyethyleneglycol ethers, and any other pharmaceutically acceptable solvents.Solubilizing agents and emulsifiers such as, without limitation: ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols, fatty acid esters of sorbitan andmixtures thereof may also be present in said compound.

Additionally, oral compound of the proposed invention can include,without limitation, adjuvants such as wetting agents, emulsifying andsuspending agents, sweetening, flavoring, coloring, and perfumingagents. When formulated as a suspension, said compound may contain theCB plant extract and suspending agents, for example, without limitation:

ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof

In one embodiment, the emulsifier may comprise a mixture ofmonoglyceride and diglyceride at a total concentration of 1% to 99% w/wand a carrageenan or mixture of carrageenans at a total concentration of0.01% to 10% w/w, in another embodiment, no carrageenans may be present.In another embodiment, the emulsifier may be present in a concentrationrange of 1% to 99%, 5% to 80%, 10% to 35%, 10% to 20%, or about 15%-25%%w/w.

Solid dosage forms suitable for oral administration include, capsules,tablets, pills, powders, and granules. In such solid dosage forms, theCB extract can be used alone or in combination with one or more drugsthat are mixed with at least one pharmaceutically acceptable excipientor carrier such as sodium citrate or dicalcium phosphate, and/or fillersor extenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid; binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;humectants such as glycerol; disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate; solution retarding agents such asparaffin; absorption accelerators such as quaternary ammonium compounds;wetting agents such as, for example, acetyl alcohol and glycerolmonostearate; absorbents such as kaolin and bentonite clay; andlubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Forcapsules, tablets and pills, in one embodiment, the dosage form can alsocomprise buffering agents.

Micellular or liposomal suspensions can be encapsulated with a varietyof polymers, sugars, and chelating agents, to yield stable solidliposomal CB preparation. Encapsulation can take the form of crosslinkedpolymers, trapping of the micells or liposomes within a non-crosslinkedpolymer network, or dispersed within the crystalline structure of sugarstarches or protein molecules. These granules can be further processedto yield sublingual films, suppositories, dispersible powder, tablets,gel capsules, and so forth.

Solid dosages in the form of tablets, capsules, pills, and granules, inone embodiment, can be coated using compounds that accelerate ordecrease the release of CBs. For instance, the proposed invention alsoencompasses solid dosage forms having enteric coatings, extended-releasecoatings, sustained-release coatings, delayed release coatings andimmediate-release coatings. Methods used to coat solid dosage forms aswell as the materials used to manufacture such coatings are well knownin the pharmaceutical formulary art. The solid dosage forms canoptionally contain opacity enhancing agents. According to an embodiment,the solid dosage form comprises an enteric coating that permits therelease of a CB or a CB analog alone or in combination with one or moredrugs at a specific location within the gastrointestinal tract,optionally, in a delayed manner. Exemplary of such coating materialsinclude glyceryl monostearate or glyceryl distearate may be employed,polymeric substances and waxes. The CB plant extract, for instance, canbe provided alone or in combination with one or more drugs that can alsobe in micro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

In one embodiments, said compound is packaged into a gelatin capsuledosage form. In another embodiment, the compound is packaged into anon-gelatin capsule or an HPMC capsule. Said capsule can be a veganbased capsule or else. The compound disclosed herein includes asustained release compound, an immediate release compound, or a combinedsustained release fraction and immediate release fraction. In oneembodiment, the therapeutic effect of the compound has a duration up to2 hours, up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours, upto 12 hours, up to 14 hours, up to 16 hours, up to 18 hours, or up to 24hours. In one embodiment, the compound disclosed herein comprises animmediate release fraction and a sustained release fraction, wherein theimmediate release fraction comprises a therapeutically effective amountof CBs and an edible oil; and wherein the sustained release fractioncomprises a therapeutically effective amount of CBs, and a mixture ofemulsifiers and other pharmacologically inactive substances.

In another embodiment, a dietary compound, according to the presentinvention, is any ingestible preparation that contains the CBsuspensions of the invention mixed with a food product. The food productcan be dried, cooked, boiled, lyophilized or baked. Breads, teas, soups,cereals, salads, sandwiches, sprouts, vegetables, animal feed, pills andtablets, are among the vast number of different food productscontemplated in the present invention.

In yet another embodiment, a compound for parenteral injection comprisespharmaceutically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions prior touse. Examples of suitable aqueous and non-aqueous carriers, diluents,solvents or vehicles include, without limitation, water, ethanol,polyols (such as glycerol, propylene glycol, polyethylene glycol, andthe like), carboxymethylcellulose and suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate.

In one embodiment, proper fluidity can be maintained, for example, bythe use of coating materials such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants. The compound of the present invention can also containadjuvants such as, but not limited to, preservatives, wetting agents,emulsifying agents, and dispersing agents. The compound for parenteraldelivery generally includes isotonic agents such as sugars, sodiumchloride, and the like. Prolonged absorption of the injectablepharmaceutical formulation can be brought about by the inclusion ofagents which delay absorption such as aluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of thespecific polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly-orthoesters andpoly-anhydrides. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable medium just prior to use.

Dosage forms for topical administration include, but are not limited to,ointments, creams, emulsions, lotions, gels, sunscreens and agents thatfavor penetration within the epidermis. Various additives, known tothose skilled in the art, may be included in the topical formulations ofthe invention. Examples of additives include, but are not limited to,solubilizers, skin permeation enhancers, preservatives (e.g.,anti-oxidants), moisturizers, gelling agents, buffering agents,surfactants, emulsifiers, emollients, thickening agents, stabilizers,humectants, dispersing agents and pharmaceutical carriers. Examples ofmoisturizers include jojoba oil and evening primrose oil.

Suitable skin permeation enhancers are well known in the art and includelower alkanols, such as methanol ethanol and 2-propanol, alkyl methylsulfoxides such as dimethylsulfoxide (DMSO), decylmethylsulfoxide (C10MSO) and tetradecylmethyl sulfoxide; pyrrolidones, urea;N,N-diethyl-m-toluamide; C2-C6 alkanediols; dimethyl formamide (DMF),N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol. Examples ofsolubilizers include, but are not limited to, hydrophilic ethers such asdiethylene glycol monoethyl ether and diethylene glycol monoethyl etheroleate; polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil,polyethylene glycol (PEG), particularly low molecular weight PEGs, suchas PEG 300 and PEG 400, and polyethylene glycol derivatives such asPEG-8 caprylic/capric glycerides; alkyl methyl sulfoxides, such as DMSO;pyrrolidones, DMA, and mixtures thereof.

Prevention and/or treatment of infections can be achieved by theinclusion of antibiotics, as well as various antibacterial andantifungal agents, for example, paraben, chlorobutanol, phenol sorbicacid, and the like, in the compounds of the invention.

One of ordinary skill will appreciate that effective amounts of theagents in the compound used in the methods of the invention can bedetermined empirically. It will be understood that, when administered toa subject, the total daily usage of the compound of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any patient will depend upon a variety of factors: the typeand degree of the response to be achieved; the activity of the specificcompound employed; the age, body weight, general health, sex and diet ofthe patient; the duration of the treatment; drugs used in combination orcoincidental with the method of the invention; and like factors wellknown in the medical arts.

The formulations of the invention, in one embodiment, are thereforeparticularly suitable for oral administration and may be administered tosubjects with a pre-existing condition or pre-disposed to certaindisease conditions, such as without limitations: autoimmune diseases anddisorders, motor neuron diseases and disorders, neurodegenerativediseases and disorders, pain associated with cancer and trauma; andother conditions, as contemplated by the invention, that include, butare not limited to: HD; Wilson's Disease; Sydenham's Chorea; ChoreaGravidarum; Autosomal Dominant Neurogenetic Syndrome; Huntington'sDisease-Like Syndrome; Prion Disease; Spinocerebellar Ataxias;Neuroacanthocytosis; Dentatorubral-Pallidoluysian Atrophy; Brain IronAccumulation Disorders; Friedreich's Ataxia; Mitochondrial Disease; RettSyndrome; Cerebrovascular Disease; PANDAS; LID; anti-convulsants andanti-psychotics drugs-related symptoms; Systemic Lupus Erythematosus;Antiphospholipid Syndrome; TS; Thyrotoxicosis; Polycythaemia Rubra Vera;Spongiform Encephalopathies; Coeliac Disease; PD; metabolic andendocrine-related diseases and disorders; athetosis-related to damage ordegeneration of basal ganglia; minor tranquilizers and alcoholwithdrawal syndromes; symptoms or side effects associated withanti-retroviral therapy, chemotherapy and radiation therapy.

In one embodiment of the proposed invention, the treatment of symptomsof motor neuron diseases involves giving to a patient in the morning byoral administration a one soft-gel capsule of the compound containing amixture that includes THC and CBD in the ratio of approximately 0.9(THC) and 2 (CBD) by weigh, and such mixture contains some amount ofother CBs, and in one embodiment, one or more non-CB components, such assesame oil, where such capsule is a time-released capsule designed torelease said mixture in the small intestine; and in another embodiment,in the stomach. The aforesaid compound and method in some subjects mayreduce symptoms associated with, in one embodiment, Wilson's Disease,having minimal to nonexistent psychotropic effect.

In another embodiment of the proposed invention, the treatment ofbenzodiazepine withdrawal symptoms involves giving to a patient beforebed time by oral administration a dose of medicament, in one embodiment,one extended release gelatin capsule and one immediate releasesoft-gelatin capsule of the compound containing a mixture of THC and CBDin the ratio of approximately 1.8 (THC) and 1.5 (CBD) by weigh, and suchmixture contains a small amount of other CBs, and in one embodiment, oneor more non-CB components, such as sesame oil. This method provideseffective control of symptoms at bed time with a moderate psychotropiceffect acting as a sleeping aid.

In another embodiment of the proposed invention, the treatment of TSsymptoms involves giving to a patient two times a day by oraladministration a dose of medicament, in one embodiment, a soft-gelatincapsule that consists of some type B and/or type A gelatin, water, and aplasticizer, such as glycerin; and encapsulates a compound containing aliquid mixture that includes: 15 mg of THC or THC analog, 20 mg of CBDor CBD analog, some sesame oil, some methyl and propyl parabens, someother cannabinoids, and less than 20% of other substances.

The potential commercial uses of the disclosed preparations include, forexample, protective/prophylactic and medical uses. The compounds of theinvention can also be administered by a variety of other routes,including mucosal, subcutaneous and intramuscular administration, andmay comprise a variety of carriers or excipients known in the formularyart, such as, non-toxic solid, semisolid or liquid filler, diluent,encapsulating material and formulation auxiliaries that arepharmaceutically acceptable.

The features disclosed in the foregoing description, or the followingclaims, or the accompanying drawings, expressed in their specific formsor in terms of a means for performing the disclosed function, or amethod or system for attaining the disclosed result, as appropriate, mayseparately, or in any combination of such features, be utilized forrealizing the invention in diverse forms thereof.

While various embodiments of the present invention have been describedabove, it should be understood that they have been presented by way ofexample only, and not limitation.

It will be understood by those skilled in the art that various changesin form and details may be made therein without departing from thespirit and scope of the invention as defined in the appended claims.Thus, the breadth and scope of the present invention should not belimited by any of the above-described exemplary embodiments, but shouldbe defined in accordance with the following claims and theirequivalents.

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What claimed is:
 1. A method of treating and/or preventing diseases anddisorders that manifest in hyper and hypokinetic movements symptoms insubjects in need thereof, the method comprising administering to thesubject a therapeutically-effective amount of a pharmaceutical compoundone or more times in 24 hours, comprising of an extract of a Cannabisplant and at least one pharmacologically inactive substance; and wheresaid extract contains at least some tetrahydrocannabinol (THC) isomerand at least some cannabidiol (CBD) isomer in the ratio of 1 (THC) and 2(CBD) by weight; and where said compound contains at least somenon-cannabinoid components consisting essentially of at least one of:terpenes; sterols; triglycerides; alkanes; squalene; tocopherol;carotenoids; chlorophyll; flavonoid; glycosides and alkaloids.
 2. Themethod of claim 1, where said extract contains at least sometetrahydrocannabinol (THC) isomer and at least some cannabidiol (CBD)isomer in the ratio of 0.5 to 1 (THC) and 1.5 to 2 (CBD) by weight. 3.The method of claim 1, where said extract contains at least sometetrahydrocannabinol (THC) isomer and at least some cannabidiol (CBD)isomer in the ratio of 1 to 1.8 (THC) and 2 to 2.5 (CBD) by weight. 4.The method of claim 1, where said compound contains one or more othercannabinoids.
 5. The method of claim 1, where said compound isadministered in a sustained release, or extended release, or a combinedsustained release and extended release fraction dosage form, or in animmediate release dosage form, or a combined sustained release fractionand immediate release fraction dosage form, or a combination thereof 6.The method of claim 1, where said compound is administered by a routeselected from the group consisting of: oral, intranasal, inhalation,parenteral, transdermal, rectal, vaginal, buccal, and sublingual, orcombination thereof
 7. The method of claim 1, where said compound isadministered in a dosage form selected from the group consisting of: atablet, a hard gelatin capsule, a soft gelatin capsule, a non-gelatincapsule, an HPMC capsule, an inhalant, an injectable, a transdermal, abuccal, a sublingual, and a rectal or a vaginal suppository.
 8. Themethod of claim 1, where said treatment involves obtaining from thesubject at least once in 90 days at least some vital signs parameters.9. The method of claim 1, where said compound is administered incombination with one or more other medications.
 10. The method of claim1, where said compound is administered for treating and/or preventingchorea, athetosis, dystonia, tremors, tics, myoclonus, stereotypies,dyskinesia, restless legs syndrome, and Periodic Limb Movement Disorder.11. The method of claim 1, where said compound is administered fortreating and/or preventing hyper and hypokinetic movement symptomsassociated with at least one of: Huntington's Disease; Wilson's Disease;Sydenham's Chorea; Chorea Gravidarum; Autosomal Dominant NeurogeneticSyndrome; Huntington's Disease-Like Syndrome; Prion Disease;Spinocerebellar Ataxias; Neuroacanthocytosis;Dentatorubral-Pallidoluysian Atrophy; Brain Iron Accumulation Disorders;Friedreich's Ataxia; Mitochondrial Disease; Rett Syndrome;Cerebrovascular Disease; Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcal Infections; Levodopa-Induced Dyskinesia,anti-convulsants and anti-psychotics drugs-related symptoms; SystemicLupus Erythematosus; Antiphospholipid Syndrome; Tourette Syndrome;Thyrotoxicosis; Polycythaemia Rubra Vera; Spongiform Encephalopathies;Coeliac Disease; Parkinson's Disease; metabolic and endocrine diseasesand disorders; athetosis-related to damage or degeneration of basalganglia; minor tranquilizers and alcohol withdrawal syndromes; symptomsor side effects associated with anti-retroviral therapy, chemotherapyand radiation therapy.
 12. The method of claim 1, where saidtetrahydrocannabinol (THC) or said cannabidiol (CBD) is one or more of:(i) natural cannabinoids that have been purified or modified; (ii)synthetically derived cannabinoids; (iii) semi-synthetic cannabinoids;(iv) esterified cannabinoids; (v) active metabolites of any of theforegoing, (vi) pro-drugs of any of the foregoing; (vii) analogs of anyof the foregoing; (viii) derivatives of any of the foregoing; (ix) andmixtures thereof
 13. The method of claim 1, where said compound is aliquid solution or liquid suspension.
 14. A pharmaceutical compound fortreating and/or preventing diseases and disorders that manifest in hyperand hypokinetic movements symptoms in subjects in need thereof,comprising of an extract of Cannabis and at least one pharmacologicallyinactive substance; and where said extract contains at least sometetrahydrocannabinol (THC) isomer and at least some cannabidiol (CBD)isomer in the ratio of 1 (THC) and 2 (CBD) by weight; and where saidcompound contains at least some non-cannabinoid components consistingessentially of at least one of: terpenes; sterols; triglycerides;alkanes; squalene; tocopherol; carotenoids; chlorophyll; flavonoid;glycosides and alkaloids.
 15. The compound of claim 14, where saidextract contains at least some tetrahydrocannabinol (THC) isomer and atleast some cannabidiol (CBD) isomer in the ratio of 0.5 to 1 (THC) and1.5 to 2 (CBD) by weight.
 16. The compound of claim 14, where saidextract contains at least some tetrahydrocannabinol (THC) isomer and atleast some cannabidiol (CBD) isomer in the ratio of 1 to 1.8 (THC) and 2to 2.5 (CBD) by weight.
 17. The compound of claim 14, where saidcompound contains one or more other cannabinoids, at least one of thefollowing: cannabigerol (CBG), Cannabichromene (CBC), cannabinol (CBN),cannabielsoin (CBE), iso-tetrahydrocannabimol (iso-THC), cannabicyclol(CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin(THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV),cannabigerovarin (CBGV) and cannabigerol monomethyl ether (CBGM), or anycombination thereof, or a natural or synthetic analogue thereof, and/orderivatives thereof
 18. The compound of claim 14, where said extract ofCannabis sativa is obtained by supercritical or subcritical extractionwith CO₂ or other chromatographic analytical techniques.
 19. Thecompound of claim 14, where said compound is packaged in a dosage formselected from the group consisting of: a tablet, a hard gelatin capsule,a soft gelatin capsule, a non-gelatin capsule, an HPMC capsule, aninhalant, a parenteral, a transdermal, a sublingual, a rectal, avaginal, and a suppository.
 20. The compound of claim 14, where saidpharmacologically inactive substance contains at least some sesame oil,or its derivative, or pharmaceutically acceptable fixed oil.
 21. Thecompound of claim 14, where said compound contains one or more othermedications.
 22. The compound of claim 14, where said compound is usedfor treating and/or preventing hyper and hypokinetic movement symptomsassociated with at least one of: Huntington's Disease; Wilson's Disease;Sydenham's Chorea; Chorea Gravidarum; Autosomal Dominant NeurogeneticSyndrome; Huntington's Disease-Like Syndrome; Prion Disease;Spinocerebellar Ataxias; Neuroacanthocytosis;Dentatorubral-Pallidoluysian Atrophy; Brain Iron Accumulation Disorders;Friedreich's Ataxia; Mitochondrial Disease; Rett Syndrome;Cerebrovascular Disease; Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcal Infections; Levodopa-Induced Dyskinesia,anti-convulsants and anti-psychotics drugs-related symptoms; SystemicLupus Erythematosus; Antiphospholipid Syndrome; Tourette Syndrome;Thyrotoxicosis; Polycythaemia Rubra Vera; Spongiform Encephalopathies;Coeliac Disease; Parkinson's Disease; metabolic and endocrine diseasesand disorders; athetosis-related to damage or degeneration of basalganglia; minor tranquilizers and alcohol withdrawal syndromes; symptomsor side effects associated with anti-retroviral therapy, chemotherapyand radiation therapy.
 23. The compound of claim 14, where saidtetrahydrocannabinol (THC) or said cannabidiol (CBD) is one or more of:(i) natural cannabinoids that have been purified or modified; (ii)synthetically derived cannabinoids; (iii) semi-synthetic cannabinoids;(iv) esterified cannabinoids; (v) active metabolites of any of theforegoing, (vi) pro-drugs of any of the foregoing; (vii) analogs of anyof the forgoing; (viii) derivatives of any of the foregoing; (ix) andmixtures thereof
 24. The compound of claim 14, where said compound is aliquid solution or liquid suspension.
 25. The compound of claim 14,where the initial purity of said tetrahydrocannabinol (THC) or saidcannabidiol (CBD) by HPLC is at least 93% by area and the stability issuch that at least 80% by area remains in undegraded form after exposureof the compound to the storage conditions for at least twelve months,where the ambient temperature is between 20° C. and 40° C. and relativehumidity is between 55% and 75%.
 26. The compound of claim 14, wheresaid compound is used for treating and/or preventing chorea, athetosis,dystonia, tremors, tics, myoclonus, stereotypies, dyskinesia, restlesslegs syndrome, and Periodic Limb Movement Disorder.
 27. A pharmaceuticalcompound for treating and/or preventing cannabinoid-responsive diseasesand disorders, comprising of a Cannabis extract or a compound containingat least 10% of natural or synthetic, or semi-synthetictetrahydrocannabinol (THC), its prodrug, its derivative, or its analog,and at least one pharmacologically inactive substance; and where saidcompound is packaged in a gelatin capsule, where said capsule does notcontain lambda-carrageenan, kappa-carrageenan, iota-carrageenan and anymixture of the carrageenans.